There are several publications related to environment-sensitive polymers and hydrogel blends, also called artificial muscles, including their application to actuating devices and drug delivery platforms. An artificial muscle is a polymer blend structured in a hydrogel network that changes its dimensions—that is deforms (e.g., swells, elongates or bends)—under the application of an environmental stimulus, e.g., pH, temperature or ionic strength gradient.
There are several patents presenting temperature-sensitive or pH-sensitive artificial muscle blends and related actuating or drug delivery devices. For example, Y. H. Bae et al. (1993) claim a pulsatile drug delivery device in U.S. Pat. No. 4,927,632. Similarly, A. Zirino (1994) claims in U.S. Pat. No. 5,334,629 the reversible controlled activation of pH-dependent fibers and gels. Also, in U.S. Pat. No. 5,904,927, M. M. Amiji (1999) synthesized a semi-interpenetrating network pH-sensitive hydrogel used for drug delivery. Unfortunately, all these and other temperature-sensitive or pH-sensitive polymer-hydrogel blends have a drastically limited use in-vivo. This is because this type of hydrogels is not selective, but rather, generally responds to any pH or temperature change occurring by any abnormality in the organism. Furthermore, in general—with very few exceptions, like that of pH gradient in the human digestive tract—one cannot create ad-hoc, or take advantage of, a natural temperature gradient or pH gradient in close proximity, or inside a living mammalian organism without risks of causing severe discomfort. In addition, there is a great need for generic drug release devices that meet each patient's needs by offering individualized therapy.
Another group of patents illustrates electro-sensitive artificial muscle blends and related actuating or drug delivery devices. For example, M. Shahinpoor (1995) outlines spring-loaded electrically controlled polymeric actuators, working in an electrolytic bath, such as a water-acetone solution, in the U.S. Pat. No. 5,389,222. Unfortunately, there is a real toxicity risk involved in using acetone solutions in proximity of living tissues, so the possibility of acetone leakage makes these gels unusable in-vivo. Also, M. Shahinpoor and K. J. Kim (2002) disclose a dry electroactive polymeric muscle in US 2002/0050454US (published patent application). Their purpose is to manufacture artificial muscles that work in dry environments, which makes them in general unusable in-vivo. M. Shahinpoor and K. J. Kim (2002) also outline novel metal hydride artificial muscles operated both electrically and thermally, for extra-corporeal, robotic, space and defense applications, including micromachines in their US published patent application 2002/0026794. Clearly, using hydrogen gas as a working fluid stored interstitially in metal hybrids is definitely not an option for artificial muscles used in direct proximity of living tissues, due to the extremely high risks involved. R. E. Pelrine and R. D. Kornbluh (2002) presented electroactive gels actuated with voltages in the order of megavolts/meter (U.S. Pat. No. 6,376,971). These extremely high voltages cannot be used in proximity of living tissues.
In terms of actuating or drug delivery devices per se, there are for example the microelectrochemical valve patented by M. J. Madou and M. J. Tierney (1994, U.S. Pat. No. 5,364,704) and the microchip drug delivery device of J. T. Santini et al. (1998, U.S. Pat. No. 6,123,861), both using the concept of a sacrificial valve: the electrochemical dissolution of a cover metal film that seals the microreservoir containing a therapeutic agent. However generic and potentially implantable, this design is for single use—that is, when a sacrificial valve is opened to release the content of the microreservoir/valve cannot be used again to deliver another dose of therapeutic agent.
Other electroactuated delivery devices use electrolytic cells for generating a controlled quantity of gas, thus causing displacement of an interface or piston that allows release of a material. For example, C. R. Bunt et al (2002, U.S. Pat. No. 6,450,991) designed such a device for intra-ruminal use.
There are also pumps and actuating devices using electroactuating polymers. For example, a synthetic muscle-based diaphragm pump is disclosed by D. Soltanpour and M. Shahinpoor (2002) in their published patent application 2002/0013545, based on the ionic polymer conductor composite polymer developed by Shahinpoor et al. However, no actuating parameters (voltage, current) and no testing data are provided.
In other cases, implantable pumps use an aqueous swellable hydrogel blend. Some publications describe continuous drug release due to an osmotic gradient through a membrane of predetermined porosity, for example the Duros implant system by J. C. Wright et al. (Journal of Controlled Release, 2001, 46, 125-148). An inherent limitation of these systems is the passive, and continuous release of the drug at a pre-determined rate.
Other release platforms are activated by hydrogels responsive to a specific chemical in the body. An example is the implantable self-regulating mechano-chemical insulin pump, by R. A. Siegel (1989, U.S. Pat. No. 5,062,841), working as a pH-sensitive gel, responsive to the pH local change generated by the oxidation of glucose to gluconic acid, biocatalyzed by the enzyme glucose oxidase immobilized in the gel network. The limitations using this approach include the available oxygen level in vivo, and the hydrogel reproducibility and lifetime. Another inconvenience is that this design is by definition limited in scope, and cannot provide a generic platform usable for all therapeutic agents.
In general, the above examples show that there is little effort devoted to the design of a generic electroactuated drug release system, which will operate at physiological pH and be able to provide adjustable drug release for personalized therapy. Thus, there is a real need for fast-acting electroactive reversible artificial muscle that will function at a wide range of pH, even at near neutral pH, and which can be configured to any desired geometry for use as an actuator in implantable drug delivery devices.